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Expression and prognostic role of E2F transcription factors in high-grade glioma.

ABSTRACT: INTRODUCTION:Patients with high-grade glioma (HGG) suffered poor survival due to inherent or acquired therapeutic resistance and refractory recurrence. The outcome of HGG patients has improved little during the past decade. Therefore, molecular signatures are urgently needed for improving diagnosis, survival prediction and identification of therapeutic targets for HGG. E2F transcription factors (E2Fs), a family of transcription factors recognized as master regulators of cell proliferation, have been found to be involved in the pathogenesis of various tumor types. AIMS:To investigate the expression of E2Fs and their prognosis value in high-grade glioma (HGG). RESULTS:Expression of E2Fs was analyzed in 394 HGG samples from TCGA dataset. E2Fs were generally expressed in HGG. Except for E2F3 and E2F5, expression of E2Fs was significantly upregulated and linked with grade progression. E2F1, E2F2, E2F7, and E2F8 were highly correlated with aggressive proliferation oncogenes, as well as potential therapeutic resistance oncogenes. Elevated E2Fs (not E2F3) were associated with adverse tumor features and poorer outcome. E2F7 and E2F8 exhibited superior outcome prediction performance compared with other E2Fs. Additionally, E2F7 and E2F8 independently predicted poorer survival in HGG patients. Gene set enrichment analysis identified a variety of critical oncogenic pathways that were tightly associated with E2F7 or E2F8, including epithelial-mesenchymal transition, NF?B, STAT3, angiogenesis pathways. Furthermore, elevated expression of E2F7 indicated worse therapeutic response of HGG to irradiation and silencing of E2F7 conferred higher cell-killing effect when combined with irradiation treatment. Mechanically, E2F7 directly regulates the transcriptional activity of EZH2 via binding at the corresponding promoter area. CONCLUSIONS:E2Fs (except for E2F3 and E2F5) are highly expressed in HGG and indicate adverse outcome. E2F7 and E2F8 were identified as novel potential prognostic markers in HGG. E2F7 was further validated to be closely associated with radioresistance of HGG and a critical transcriptional regulator of EZH2.

SUBMITTER: Yu H

PROVIDER: S-EPMC7299000 | biostudies-literature | 2020 Jul

REPOSITORIES: biostudies-literature

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Expression and prognostic role of E2F transcription factors in high-grade glioma.

Yu Hai H Li Zhijin Z Wang Maode M

CNS neuroscience & therapeutics 20200216 7

<h4>Introduction</h4>Patients with high-grade glioma (HGG) suffered poor survival due to inherent or acquired therapeutic resistance and refractory recurrence. The outcome of HGG patients has improved little during the past decade. Therefore, molecular signatures are urgently needed for improving diagnosis, survival prediction and identification of therapeutic targets for HGG. E2F transcription factors (E2Fs), a family of transcription factors recognized as master regulators of cell proliferatio ...[more]

PMID: 32064771

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Project description:BackgroundE2F transcription factors (E2Fs) are a group of genes encoding a family of transcription factors in higher eukaryotes. They are involved in a variety of cellular functions and are up-regulated in many tissues and organs. However, the expression level, genetic variation, molecular mechanism, and biological function of different E2Fs in PAAD and its relationship with the prognosis and immune infiltration in patients with PAAD have not been fully elucidated.MethodsIn this study, we investigated the mRNA expression level, genetic variation, prognostic value and gene-gene interaction network of E2Fs in PAAD using the Oncomine, GEPIA, Kaplan Meier plotter, cBioPortal, GeneMANIA, STRING and Metascape database. Then, the relationship between E2Fs expression and tumor immune invasion was studied by using the TIMER database. Finally, we confirmed the expression of E2Fs in PAAD by IHC.ResultsThe transcription levels of E2F1/3/5/8 are obviously up-regulated in PAAD and the high expression of E2F2/3/6/8 was apparently associated with the tumor stage of patients with PAAD. The abnormal expression of E2F1/2/3/4/5/7/8 in PAAD patients is related to the clinical outcome of PAAD patients. We also found that PAAD tissues have higher expression levels of E2F1/3/5/8 compared with adjacent normal tissues. The function of E2Fs and its neighboring genes is mainly related to the transcription initiation of the RNA polymerase II promoter. The functions of E2Fs and its neighboring proteins are mainly related to cell cycle, virus carcinogenesis, FoxO signaling pathway, TGF-β signaling pathway, transcriptional disorders in cancer and Wnt signaling pathway. We also found that the expression of E2Fs was significantly correlated with immune infiltrates, including B cells, CD8+ T cells, CD4+T cells, neutrophils, macrophages, and dendritic cells.ConclusionsOur study may provide new insights into the choice of immunotherapy targets and prognostic biomarkers in PAAD patients.

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Expression and prognostic role of E2F transcription factors in high-grade glioma.

Publications

Expression and prognostic role of E2F transcription factors in high-grade glioma.

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